CN102580056A - Controlled-release injection containing antidiuresis components and preparation method thereof - Google Patents

Abstract

The invention relates to a controlled-release injection containing antidiuresis components and a preparation method thereof. The controlled-release injection contains main drugs of desmopressin acetate, sustained release auxiliary materials, suspending agent and menstruum. The sustained release auxiliary materials are selected from polylactic acid, polylactic acid-co-glycolic acid, ethylene-vinyl acetate copolymer, polifeprosan and the like, which can be used for slowly releasing medicine into disease local parts in a degrading and absorbing process, so that general toxicity reaction is obviously reduced, and simultaneously, the effective medicine concentration can be maintained on the disease local parts; the suspending agent is selected from sodium carboxymethylcellulose, mannitol and the like, which is used for suspending sustained-release granules or microspheres of biological active ingredients; and the menstruum is common menstruum or special menstruum containing the suspending agent, wherein the common menstruum is selected from distilled water, water for injection, physiological lotion, absolute ethyl alcohol or buffer solution prepared by various salts, and the like. According to the controlled-release injection, the action time of the medicine can be prolonged, the dosage times are reduced, the stability of blood drug concentration in vivo is maintained, and the drug toxic and side effects are reduced.

Description

A kind of sustained release injection containing antidiuretic component and preparation method thereof

Technical field:

The invention relates to the field of preparations, in particular to a slow-release injection containing antidiuretic components and a preparation method thereof.

Background technique:

Desmopressin (Desmopressin) is a synthetic analogue of the natural hormone arginine vasopressin, which has a high degree of anti-urination activity and is used for the treatment of urinary system diseases. Natural human arginine vasopressin is a 9-peptide, the 1st and 6th cysteines are connected by disulfide bonds to form a ring structure, the 1st and 9th positions have an amino group, and the 8th position is L-arginine. Desmopressin has two modifications to the structure of natural molecules, one is to remove the amino group at position 1, and the other is to replace L-arginine at position 8 with D-arginine, namely 1-deamino-8-D - Arginine vasopressin (1-deamino-8-D-arginine vasoprssin, DDAVP). This structural modification greatly enhanced the ability of the molecule to resist enzymatic degradation, enhanced antidiuretic effect, prolonged duration of action, and significantly reduced vasopressor effect. The antidiuretic/pressor activity ratio of desmopressin is 2000-3000 times greater than that of the parent molecule, and the drug effect can be maintained for 10-12 hours, while the parent molecule only has 2-3 hours. In addition, larger doses of vasopressin can also increase the level of coagulation factor VIII and have a hemostatic effect.

More than 20 years of clinical application have proved that no matter its nasal drops, sprays or oral tablets have achieved good curative effect, with few side effects, it is unanimously recognized that desmopressin is the drug of choice for the treatment of central diabetes insipidus. Although the existing desmopressin preparations can meet the needs of patients, they still need to be improved. Tablets usually need to be taken with water, whereas treatment with desmopressin must limit fluid intake, and when ingested in tablet form, the bioavailability of desmopressin is approximately equivalent to 0.1% of intravenous injection. Intranasal administration resulted in higher bioavailability but lower patient acceptance. Moreover, intranasal administration may have adverse effects on cilia, making it easier for viruses and bacteria to enter the mucosa. Frequent administration of injections is inconvenient for clinical use and medication for patients.

The invention aims at the shortcomings of the existing preparations, and provides a sustained-release injection with desmopressin acetate as an active ingredient. The slow-release injection can prolong the action time of the drug, reduce the frequency of medication and drug tolerance, maintain a relatively stable blood drug concentration in the body, reduce the toxic and side effects of the drug, and improve the patient's compliance.

Invention content:

The purpose of the present invention is to prepare a sustained-release injection with desmopressin acetate as an active ingredient, which has the advantages of prolonging the drug action time, reducing the number of medications and drug tolerance, maintaining a relatively stable blood drug concentration in the body, and reducing drug toxicity. Toxic and side effects, improve patient compliance and other advantages.

The present invention has prepared a sustained-release injection containing desmopressin acetate medicine, which comprises the main drug desmopressin acetate, sustained-release auxiliary materials, suspending agents and solvents; the sustained-release injection includes the following components:

(A) The sustained-release microparticles are composed of the following components, all in weight percentage: 0.5-60% of the main drug desmopressin acetate, 40-99.5% of the sustained-release auxiliary material, and 0.0-30% of the suspending agent;

(B) Solvents are divided into ordinary solvents or special solvents.

The present invention prepares a slow-release injection containing desmopressin acetate medicine, and its slow-release auxiliary materials are selected from polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), ethylene vinyl acetate copolymer, poly Propylene Glycol, Racemic Polylactic Acid, Racemic Polylactic Acid/Glycolic Acid Copolymer, Monomethyl Polyethylene Glycol/Polylactic Acid, Monomethyl Polyethylene Glycol/Polylactic Acid Copolymer, Polyethylene Glycol/ Polylactic acid, polyethylene glycol/polylactic acid copolymer, carboxy-terminated polylactic acid, polydioxanone, polytrimethylene carbonate, xylitol, oligosaccharides, chondroitin, chitin, hyaluronic acid , collagen, gelatin, protein glue or a combination thereof; its suspending agent is selected from sodium carboxymethylcellulose, (iodo)glycerin, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant Substance, one of Tween 20, Tween 40 and Tween 80 or a combination thereof; the solvent is divided into common solvent or special solvent, common solvent is selected from distilled water, water for injection, physiological flushing solution, absolute ethanol or various salt preparations buffer solution; when the suspending agent in the slow-release microparticles is "0", the solvent is a special solvent, and the special solvent is a common solvent containing a suspending agent, and the suspending agent is selected from sodium carboxymethylcellulose, (iodine) Glycerin, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, one of Tween 20, Tween 40 and Tween 80 or a combination thereof.

Through a large number of optimization experiments, the present invention has found the most optimal formula composition. Among them, the weight percentage of its main drug desmopressin acetate is preferably 10%-50%; its sustained-release auxiliary materials are preferably 50%-90% PLA, 50%-90% PLGA (3:1); its suspending agent is preferably 1.5% sodium carboxymethylcellulose, 1.5% sodium carboxymethylcellulose and 0.1% Tween 80, 1.5% sodium carboxymethylcellulose and 15% sorbitol and 0.1% Tween 80.

In addition, the present invention also provides a method for preparing desmopressin acetate sustained-release injection, the steps of which are as follows:

or

or

or

(D) First mix the sustained-release microparticles with a special solvent to prepare a corresponding suspension, then use vacuum drying to remove the water in the suspension, and then suspend with a special or common solvent to obtain the corresponding slow-release microparticles. released microparticle injections.

Description of drawings:

Accompanying drawing 1, accompanying drawing 2, accompanying drawing 3, accompanying drawing 4 are the drug release degree-release time graphs of desmopressin acetate in the sustained-release injection of each embodiment respectively.

Detailed ways:

The present invention includes but is not limited to the following examples.

Example 1:

The main drug desmopressin acetate is 20mg, PLA is 80mg, and the special solvent is 1.5% sodium carboxymethylcellulose in normal saline.

Its preparation process is as follows:

Put 80mg of polylactic acid (PLA) into a container, add 100ml of dichloromethane, dissolve and mix well, add 20mg of desmopressin acetate, reshake well, and then vacuum dry to remove the organic solvent. The dried drug-containing solid composition is frozen and pulverized to make sustained-release microparticles containing 20% desmopressin acetate, and then suspended in 5000ml of physiological saline containing 1.5% (percentage by weight) sodium carboxymethylcellulose to prepare Get the corresponding suspension type sustained-release injection.

5000 bottles of desmopressin acetate sustained-release injections were prepared in this example, and each bottle contained 4 μg of the main drug (1 ml/bottle). Through the determination of the release degree, the sustained-release effect and clinical drug safety were investigated.

Accurately weigh several portions of the desmopressin acetate sustained-release microparticles prepared in Example 1, 5 mg in each portion, and place in 35 10 mL vials, and add NaHPO ₄ and 0.1M NaH to _each portion. _{2 PO4} pH7.4 phosphate buffer solution, placed in a constant temperature water bath at 37°C, taken out on days 0, 4, 8, 12, 16, 20, 24, 28, and 32, centrifuged, and redispersed in dichloro Methane acetate buffer solution (1: 1v/v), the chromatographic column is C1850 × 2mm, the mobile phase is 1: 1 containing 0.1% trifluoroacetic acid and 50% acetonitrile mixed solution containing 1% trifluoroacetic acid, flow rate 1.0ml/ min, detect at 240nm, measure the residual drug amount in the microparticles, calculate the cumulative release according to the external standard method, the in vitro drug release assay results of the desmopressin acetate sustained-release microparticle preparation prepared in Example 1 are as shown in Table 1:

The in vitro drug release test results of the desmopressin acetate sustained-release microsphere preparation prepared in Table 1 Example 1

Taking the release time as the abscissa and the cumulative release as the ordinate, the in vitro drug release curve of the desmopressin acetate sustained-release microparticle preparation prepared in Example 1 was drawn, and the results are shown in Figure 1 of the specification.

Example 2:

20mg main drug desmopressin acetate, 80mg PLA, special solvent is 1.5% sodium carboxymethylcellulose and 0.1% Tween 80 normal saline. Its preparation process is as follows:

Put 80mg of polylactic acid (PLA) into a container, add 100ml of dichloromethane, dissolve and mix well, add 20mg of desmopressin acetate, reshake well, and then vacuum dry to remove the organic solvent. The dried drug-containing solid composition is frozen and pulverized to make slow-release microparticles containing 20% desmopressin acetate, and then suspended in 5000ml containing 1.5% (weight percent) sodium carboxymethylcellulose and 0.1% Tween 80 The corresponding suspension-type sustained-release injection was prepared in normal saline.

5000 bottles of desmopressin acetate sustained-release injections were prepared in this example, and each bottle contained 4 μg of the main drug (1 ml/bottle). Through the determination of the release degree, the sustained-release effect and clinical drug safety were investigated.

Accurately weigh several portions of the desmopressin acetate sustained-release microparticles prepared in Example 2, 5 mg in each portion, and place in 35 10 mL vials, and add NaHPO ₄ and 0.1M NaH to _each portion. _{2 PO4} pH7.4 phosphate buffer solution, placed in a constant temperature water bath at 37°C, taken out on days 0, 4, 8, 12, 16, 20, 24, 28, and 32, centrifuged, and redispersed in dichloro Methane acetate buffer solution (1: 1v/v), the chromatographic column is C1850 × 2mm, the mobile phase is 1: 1 containing 0.1% trifluoroacetic acid and 50% acetonitrile mixed solution containing 1% trifluoroacetic acid, flow rate 1.0ml/ min, detect at 240nm, measure the residual drug amount in the microparticles, calculate the cumulative release according to the external standard method, the in vitro drug release assay results of the desmopressin acetate sustained-release microparticle preparation prepared in Example 2 are as shown in Table 2:

The in vitro drug release test results of the desmopressin acetate sustained-release microsphere preparation prepared by the embodiment 2 of table 2

Taking the release time as the abscissa and the cumulative release as the ordinate, the in vitro drug release curve of the desmopressin acetate sustained-release microparticle preparation prepared in Example 2 was drawn, and the results are shown in Figure 2 of the specification.

Example 3:

20mg main drug desmopressin acetate, 80mg PLA, special solvent is 1.5% sodium carboxymethylcellulose, 15% sorbitol and 0.1% Tween 80 normal saline. Its preparation process is as follows:

Put 80mg of polylactic acid (PLA) into a container, add 100ml of dichloromethane, dissolve and mix well, add 20mg of desmopressin acetate, reshake well, and then vacuum dry to remove the organic solvent. The dried drug-containing solid composition is frozen and pulverized to make slow-release microparticles containing 20% desmopressin acetate, and then suspended in 5000ml containing 1.5% (percentage by weight) sodium carboxymethylcellulose and 15% sorbitol and 0.1 % Tween 80 in normal saline to prepare the corresponding suspension-type sustained-release injection.

5000 bottles of desmopressin acetate sustained-release injections were prepared in this example, and each bottle contained 4 μg of the main drug (1 ml/bottle). Through the determination of the release degree, the sustained-release effect and clinical drug safety were investigated.

Accurately weigh several portions of the desmopressin acetate sustained-release microparticles prepared in Example 3, 5 mg in each portion, and place in 35 10 mL vials, and add NaHPO ₄ and 0.1M NaH to _each portion. _{2 PO4} pH7.4 phosphate buffer solution, placed in a constant temperature water bath at 37°C, taken out on days 0, 4, 8, 12, 16, 20, 24, 28, and 32, centrifuged, and redispersed in dichloro Methane acetate buffer solution (1: 1v/v), the chromatographic column is C1850 × 2mm, the mobile phase is 1: 1 containing 0.1% trifluoroacetic acid and 50% acetonitrile mixed solution containing 1% trifluoroacetic acid, flow rate 1.0ml/ min, detect at 240nm, measure the residual drug amount in the microparticle, calculate the cumulative release according to the external standard method, the in vitro drug release assay results of the desmopressin acetate sustained-release microparticle preparation prepared in Example 3 are as shown in Table 3:

The in vitro drug release test result of the desmopressin acetate sustained-release microsphere preparation prepared by the embodiment 3 of table 3

Taking the release time as the abscissa and the cumulative release as the ordinate, the in vitro drug release curve of the desmopressin acetate sustained-release microparticle preparation prepared in Example 3 was drawn, and the results are shown in Figure 3 of the specification.

Example 4:

20mg main drug desmopressin acetate, 80mg PLGA (3:1), the special solvent is 1.5% sodium carboxymethylcellulose, 15% sorbitol and 0.1% Tween 80 normal saline. Its preparation process is as follows:

Put 80mg of polylactic-co-glycolic acid (PLGA, 3:1) into a container, add 100ml of dichloromethane, dissolve and mix well, add 20mg of desmopressin acetate, re-shake, and then vacuum-dry to remove the organic solvent . The dried drug-containing solid composition is frozen and pulverized to make slow-release microparticles containing 20% desmopressin acetate, and then suspended in 5000ml containing 1.5% (percentage by weight) sodium carboxymethylcellulose and 15% sorbitol and 0.1 % Tween 80 in normal saline to prepare the corresponding suspension-type sustained-release injection.

5000 bottles of desmopressin acetate sustained-release injections were prepared in this example, and each bottle contained 4 μg of the main drug (1 ml/bottle). Through the determination of the release degree, the sustained-release effect and clinical drug safety were investigated.

Accurately weigh several portions of the desmopressin acetate sustained-release microparticles prepared in Example 4, 5 mg in each portion, and place in 35 10 mL vials, and add NaHPO ₄ and 0.1M NaH to _each portion. _{2 PO4} pH7.4 phosphate buffer solution, placed in a constant temperature water bath at 37°C, taken out on days 0, 4, 8, 12, 16, 20, 24, 28, and 32, centrifuged, and redispersed in dichloro Methane acetate buffer solution (1: 1v/v), the chromatographic column is C1850 × 2mm, the mobile phase is 1: 1 containing 0.1% trifluoroacetic acid and 50% acetonitrile mixed solution containing 1% trifluoroacetic acid, flow rate 1.0ml/ min, detect at 240nm, measure the residual drug amount in the microparticle, calculate the cumulative release according to the external standard method, the in vitro drug release assay results of the desmopressin acetate sustained-release microparticle preparation prepared in Example 3 are as shown in Table 3:

The in vitro drug release test result of the desmopressin acetate sustained-release microsphere preparation prepared by the embodiment 4 of table 4

Taking the release time as the abscissa and the cumulative release as the ordinate, the in vitro drug release curve of the desmopressin acetate sustained-release microparticle preparation prepared in Example 4 was drawn, and the results are shown in Figure 4 of the specification.

Claims (10)

1. A sustained-release injection containing antidiuretic components and a preparation method thereof, characterized in that the sustained-release injection comprises principal agent desmopressin acetate, sustained-release auxiliary materials, suspending agents and solvents; the sustained-release injection comprises the following Components: (A) The sustained-release microparticles are composed of the following components, all in weight percentage: 0.5-60% of the main drug desmopressin acetate, 40-99.5% of the sustained-release auxiliary material, and 0.0-30% of the suspending agent; (B) Solvents are divided into ordinary solvents or special solvents. 2. the described preparation of claim 1, its slow-release auxiliary material is selected from polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), ethylene vinyl acetate copolymer, polyphenylene propane, racemic polylactic acid, Racemic Polylactic/Glycolic Acid Copolymer, Monomethylpolyethylene Glycol/Polylactic Acid, Monomethylpolyethylene Glycol/Polylactic Acid Copolymer, Polyethylene Glycol/Polylactic Acid, Polyethylene Glycol/Polylactic Acid One of copolymer, carboxyl-terminated polylactic acid, polydioxanone, polytrimethylene carbonate, xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin, protein glue or a combination thereof. 3. the described preparation of claim 1, its suspending agent is selected from sodium carboxymethyl cellulose, (iodo) glycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20 , one or a combination of Tween 40 and Tween 80. 4. the described preparation of claim 1, its solvent is divided into common solvent or special solvent, common solvent is selected from the buffer solution of distilled water, water for injection, physiological wash solution, dehydrated alcohol or various salt preparation; When the suspending agent is "0", the solvent is a special solvent, and the special solvent is an ordinary solvent containing a suspending agent. The suspending agent is selected from sodium carboxymethylcellulose, (iodo)glycerin, simethicone, propylene glycol, carbopol Mu, mannitol, sorbitol, surfactant, one of Tween 20, Tween 40 and Tween 80 or a combination thereof. 5. the described preparation of claim 1-4, the preferred 10%-50% of the percentage by weight of its principal agent desmopressin acetate; Its sustained-release auxiliary material is preferably 50%-90% PLA, 50%-90% PLGA (3 : 1); Its suspending agent preferably 1.5% sodium carboxymethyl cellulose, 1.5% sodium carboxymethyl cellulose and 0.1% Tween 80, 1.5% sodium carboxymethyl cellulose and 15% sorbitol and 0.1% Tween 80. 6. the described preparation of claim 6, its formula consists of: 20mg principal agent desmopressin acetate, 80mg PLA, special solvent is the physiological saline of 1.5% sodium carboxymethyl cellulose. 7. the described preparation of claim 6, its formula consists of: 20mg principal agent desmopressin acetate, 80mg PLA, special solvent is the normal saline of 1.5% sodium carboxymethylcellulose and 0.1% Tween 80. 8. The described preparation of claim 6, its prescription is composed of: 20mg principal agent desmopressin acetate, 80mg PLA, special solvent is the physiologic agent of 1.5% sodium carboxymethylcellulose and 15% sorbitol and 0.1% Tween 80. brine. 9. the described preparation of claim 6, its formula consists of: 20mg principal agent desmopressin acetate, 80mg PLGA (3: 1), special solvent is 1.5% sodium carboxymethylcellulose and 15% sorbitol and 0.1% Tween 80 saline. 10. the described preparation of claim 1, the preparation method of its sustained-release injection, the steps are as follows: or or or (D) First mix the sustained-release microparticles with a special solvent to prepare a corresponding suspension, then use methods such as vacuum drying to remove the water in the suspension, and then suspend with a special solvent or a common solvent to obtain the corresponding slow-release microparticles. released microparticle injections.

Images